U.S. patent application number 12/394872 was filed with the patent office on 2009-06-18 for methods and compositions for the treatment of autoimmune disorders using clofarabine.
Invention is credited to Stuart William Gordon Smith, Christopher B. Wood.
Application Number | 20090155211 12/394872 |
Document ID | / |
Family ID | 32043399 |
Filed Date | 2009-06-18 |
United States Patent
Application |
20090155211 |
Kind Code |
A1 |
Wood; Christopher B. ; et
al. |
June 18, 2009 |
Methods and Compositions for the Treatment of Autoimmune Disorders
Using Clofarabine
Abstract
This invention relates to methods of treating or preventing an
autoimmune disorder comprising the administration of clofarabine or
a pharmaceutically acceptable salt, hydrate, solvate, clathrate,
prodrug or metabolite thereof to a patient in need of such
treatment. The invention further relates to methods of treating or
preventing an autoimmune disorder comprising the administration of
clofarabine or a pharmaceutically acceptable salt, hydrate,
solvate, clathrate, prodrug or metabolite thereof and an additional
therapeutic agent to a patient in need of such treatment.
Inventors: |
Wood; Christopher B.; (Stoke
Poges, GB) ; Smith; Stuart William Gordon;
(Stirlingshire, GB) |
Correspondence
Address: |
GENZYME CORPORATION;LEGAL DEPARTMENT
15 PLEASANT ST CONNECTOR
FRAMINGHAM
MA
01701-9322
US
|
Family ID: |
32043399 |
Appl. No.: |
12/394872 |
Filed: |
February 27, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10529519 |
Aug 24, 2005 |
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PCT/US03/30409 |
Sep 25, 2003 |
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12394872 |
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60414687 |
Sep 27, 2002 |
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Current U.S.
Class: |
424/85.6 ;
514/1.1; 514/45; 536/27.7 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/724 20130101; A61K 31/70 20130101; A61K 31/34 20130101;
A61P 17/00 20180101; A61P 37/06 20180101; A61K 31/7076 20130101;
A61K 31/34 20130101; A61K 2300/00 20130101; A61K 31/70 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
424/85.6 ;
514/45; 514/12; 536/27.7 |
International
Class: |
A61K 38/21 20060101
A61K038/21; A61K 31/7076 20060101 A61K031/7076; A61K 38/16 20060101
A61K038/16; C07H 19/16 20060101 C07H019/16; A61P 37/06 20060101
A61P037/06 |
Claims
1. A method of treating, managing or preventing an autoimmune
disorder which comprises administering to a patient in need of such
treatment a therapeutically or prophylactively effective amount of
clofarabine or a pharmaceutically acceptable salt, stereoisomer,
solvate, hydrate, clathrate, prodrug or metabolite thereof.
2. The method of claim 1 wherein the autoimmune disorder is a
disorder of the nervous system, the blood, the gastrointestinal
system, the endocrine glands, the skin, the musculoskeletal system,
the connective tissue or combinations thereof
3. The method of claim 1 wherein the autoimmune disorder is
Alopecia Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome,
Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia,
Autoimmune Hepatitis, Autoimmune Uveitis, Autoimmune Oophoritis,
Autoimmune Orchitis, Behcet's Disease, Bullous Pemphigoid,
Cardiomyopathy, Celiac Sprue Dermatitis, Chronic Fatigue Immune
Dysfunction Syndrome (CFIDS), Chronic Inflammatory Demyelinating
Polyneuropathy, Churg Strauss Syndrome, Cicatricial Pemphigoid,
CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease,
Dermatitis Herpetiformis, Essential Mixed Cryoglobulinemia,
Fibromyalgia Fibromyositis, Graves' Disease, Guillain Barre,
Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic
Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin dependent
Diabetes, Immune Mediated Diabetes, Juvenile Arthritis, Lichen
Planus, Meniere's Disease, Mixed Connective Tissue Disease,
Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia,
Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes,
Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary
Agammag lobulinemia, Primary Biliary Cirrhosis, Psoriasis,
Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever,
Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiff Man Syndrome,
Takayasu Arteritis, Temporal Arteritis, Giant Cell Arteritis,
Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo or Wegener's
Granulomatosis.
4. The method of claim 1 wherein the patient is a mammal.
5. The method of claim 4 wherein the mammal is a human.
6. The method of claim 5 wherein the human is an adult.
7. The method of claim 5 wherein the human is an adolescent.
8. The method of claim 5 wherein the human is a child.
9. The method of claim 5 wherein the human is an infant.
10. The method of claim 1 further comprising the administration of
an additional therapeutic agent.
11. The method of claim 10 wherein the additional therapeutic agent
is an antibiotic, an antiemetic agent, an antidepressant, and
antifungal agent, an antiinflammatory agent, an antiviral agent, an
immunomodulatory agent, a .beta.-interferon, an alkylating agent, a
hormone or a cytokine.
12. The method of claim 1 wherein the therapeutically or
prophylactively effective amount is greater than 1 mg/kg/day.
13. The method of claim 1 wherein the therapeutically or
prophylactively effective amount of clofarabine is from about 5
mg/kg/day to about 75 mg/kg/day.
14. The method of claim 13 wherein the therapeutically or
prophylactively effective amount of clofarabine is from about 20
mg/kg/day to about 60 mg/kg/day.
15. The method of claim 14 wherein the therapeutically or
prophylactively effective amount of clofarabine is from about 40
mg/kg/day to about 50 mg/kg/day.
16. The method of claim 1 wherein the therapeutically or
prophylactively effective amount of clofarabine is administered
parenterally.
17. The method of claim 1 wherein the therapeutically or
prophylactively effective amount of clofarabine is administered
orally.
18. A dosage form which comprises clofarabine or a pharmaceutically
acceptable prodrug, salt, stereoisomer, solvate, hydrate,
clathrate, prodrug or metabolite thereof.
19. The dosage form of claim 18 wherein said dosage form is
suitable for parenteral, transdermal, mucosal or oral
administration to a patient.
20. The dosage form of claim 19 wherein said mucosal administration
is nasal administration.
21. The dosage form of claim 19 wherein said mucosal administration
is buccal administration.
22. The dosage form of claim 19 wherein said mucosal administration
is sublingual administration.
23. The dosage form of claim 19 wherein said mucosal administration
is rectal administration.
24. The dosage form of claim 19 wherein said dosage form is a
capsule or a tablet.
25. The dosage form of claim 19 wherein said dosage form is an
aerosol.
26. The dosage form of claim 19 wherein said dosage form is a
reconstitutable powder.
27. The dosage form of claim 18 wherein the amount of clofarabine
is from about 5 mg to about 1000 mg.
28. The dosage form of claim 27 wherein the amount of clofarabine
is from about 100 mg to about 500 mg.
29. The dosage form of claim 28 wherein the amount of clofarabine
is from about 200 mg to about 350 mg.
30. The dosage form of claim 18 wherein the dosage form is
sterile.
31. A high dose pharmaceutical composition for the treatment of an
autoimmune disorder which comprises about 5 to about 1000 mg of
clofarabine, or a pharmaceutically acceptable salt, hydrate,
clathrate, solvate, prodrug, metabolite or stereoisomer thereof and
a pharmaceutically acceptable carrier.
32. A method of treating multiple sclerosis which comprises
administering to a patient in need of such treatment from about
1.25 mg/kg/day to about 80 mg/kg/day of clofarabine or a
pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,
clathrate, prodrug or metabolite thereof.
33. The method of claim 32 which comprises administering from about
50 mg/kg/day to about 75 mg/kg/day of clofarabine or a
pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,
clathrate, prodrug or metabolite thereof.
34. The method of claim 33 which comprises administering from about
20 mg/kg/day to about 60 mg/kg/day of clofarabine or a
pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,
clathrate, prodrug or metabolite thereof.
35. The method of claim 33 which comprises administering from about
40 mg/kg/day to about 50 mg/kg/day of clofarabine or a
pharmaceutically acceptable salt, stereoisomer, solvate, hydrate,
clathrate, prodrug or metabolite thereof.
36. The method of claim 32 wherein the therapeutically or
prophylactively effective amount of clofarabine is administered
parenterally.
37. The method of claim 32 wherein the therapeutically or
prophylactively effective amount of clofarabine is administered
orally.
Description
1. FIELD OF THE INVENTION
[0001] This invention relates to pharmaceutical compositions,
dosage forms and dosage regimens utilizing clofarabine. This
invention also relates to methods of treating autoimmune disorders,
and to methods for dosing clofarabine, each of these methods also
encompasses reducing or avoiding undesired effects associated with
conventional treatment of autoimmune disorders.
2. BACKGROUND OF THE INVENTION
2.1 Autoimmune Disorders
[0002] The immune system is a complicated network of cells and cell
components that defend the body and eliminate infections caused by
bacteria, viruses, and other invading microbes. Autoimmune
disorders, however, cause the immune system to mistakenly attack
the cells, tissues, and organs of a patient's own body.
[0003] There are many different autoimmune diseases, and they can
each affect the body in different ways. Autoimmune disorders can
target specific organs and tissues in the body, e.g., the brain, as
in Multiple Sclerosis, or the gastrointestinal system as in Crohn's
disease. In other cases, autoimmune disorders can affect a variety
of tissues in the same patient or from patient to patient.
Additionally, autoimmune disorders can have permanent effects on
the body, such as in the causal role of Type I, insulin dependent
diabetes.
[0004] Some autoimmune diseases are known to begin or worsen with
certain triggers such as viral infections. It is important to be
aware of the factors that can be avoided to help prevent or
minimize the amount of damage from the autoimmune disease. Other
less understood influences affecting the immune system and the
course of autoimmune diseases include aging, chronic stress,
hormones and pregnancy.
[0005] Traditional medications slow or suppress the immune system
response in an attempt to stop the inflammation involved in the
autoimmune attack. For example, medication can slow or stop the
immune system's destruction of the kidneys or joints. These drugs
include corticosteroids (prednisone), methotrexate,
cyclophosphamide, azathioprine, and cyclosporins. Unfortunately,
these medications also suppress the ability of the immune system to
fight infection and have other potentially serious side
effects.
[0006] A current goal in caring for patients with autoimmune
diseases is to find treatments that produce remissions with fewer
side effects.
2.2 Clofarabine
[0007] Purine nucleosides have been previously reported as useful
for the treatment of cancers. An exemplary class of purine
nucleosides and their potential use in anti-cancer therapy is
disclosed in U.S. Pat. Nos. 4,751,221 and 4,918,179. Subsequently,
the specific nucleosides fludarabine and clofarabine and their
proposed utility as cytotoxic compounds were described in U.S. Pat.
Nos. 5,304,518; 5,384,310 and 5,661,136.
[0008] Clofarabine is an adenosine nucleoside analogue which is
chemically named 2 Chloro 9 (2 deoxy 2 fluoro .beta. D
arabinofuranosyl)adenine [CL-F-Ara-A]. Shortnacy Fowler A T, Tiwari
K N, Montgomery J A, et al. Synthesis and biological activity of 4'
C hydroxymethyl 2' fluoro D arabinofuranosylpurine nucleosides.
Nucleosides Nucleotides Nucleic Acids 20(8):1583 98, 2001.
##STR00001##
Clofarabine appears to have multiple mechanisms of action against
cancer, including inhibiting both DNA polymerases and
ribonucleotide reductase and inducing apoptosis. It also appears to
be effective against certain cancers through a unique additional
mechanism, whereby it directly damages the mitochondria in cancer
cells and induces apoptosis (Genini D, Adachi S, Chao Q, et al.
Blood 2000 96: 3537).
[0009] Clofarabine is also known by the tradename CLOFAREX, and is
being developed for the acute treatment of myelogenous leukemia in
adults, for acute lymphocytic leukemia in children and for the
treatment of advanced solid tumors in adults. Johnson S A.
Nucleoside analogues in the treatment of hematological
malignancies. Expert Opin Pharmacother 2(6):929-43, 2001.
[0010] Recently, certain nucleoside analogs have been reported to
have potential utility at low doses (0.04 to about 0.20 mg/kg/day)
in treating autohemyltic anemia (U.S. Pat. No. 5,106,837);
rheumatoid arthritis (U.S. Pat. No. 5,31,732); and inflammatory
Bowel Disease (U.S. Pat. No. 5,506,213). Furthermore, a class of
nucleoside analogs have been reported to have potential utility in
the treatment of multiple sclerosis at doses from about 0.04 to
about 0.20 mg/kg per day (U.S. Pat. No. 5,506,214).
[0011] Clofarabine is an interesting anticancer drug candidate.
However, all of the potential uses for clofarabine have thus far
remained unexplored or undeveloped. Further, there remains a need
for high dosage compositions. Also, as discussed above, treatments
for autoimmune disorders are needed. Finally, dosing regimens,
particularly for the use of clofarabine in the treatment of
diseases other than cancer are needed.
3. SUMMARY OF THE INVENTION
[0012] This invention encompasses compositions comprising, and
methods of using, clofarabine, and pharmaceutically acceptable
salts, stereoisomers, solvates, hydrates and clathrates
thereof.
[0013] A first embodiment of the invention encompasses a method of
treating, preventing or managing an autoimmune disorder which
comprises administering to a patient in need of such treatment a
therapeutically or prophylactively effective amount of clofarabine
or a pharmaceutically acceptable salt, solvate, hydrate, or
clathrate thereof. In a specific embodiment of the invention, the
autoimmune disorder is a disorder of the nervous system, the blood,
the gastrointestinal system, the endocrine glands, the skin, the
musculoskeletal system, the connective tissue or combinations
thereof. Significantly, the invention encompasses novel doses and
dosing regimens for treating autoimmune disorders. In particular,
doses higher than those previously contemplated in the art are used
chronically or periodically and in cycling therapy to treat or
prevent autoimmune disorders. A preferred embodiment is to treat
multiple sclerosis with doses higher than previously contemplated
in the art.
[0014] In a preferred embodiment, the invention encompasses the
treatment, prevention or management of certain specific autoimmune
disorders including, but not limited to, Alopecia Areata,
Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune
Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune
Hepatitis, Autoimmune Uveitis, Autoimmune Oophoritis, Autoimmune
Orchitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy,
Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction
Syndrome (CFIDS), Chronic Inflammatory Demyelinating
Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid,
CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease,
Dermatitis Herpetiformis, Essential Mixed Cryoglobulinemia,
Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barre,
Hashimoto's Thyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic
Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin dependent
Diabetes, Immune Mediated Diabetes, Juvenile Arthritis, Lichen
Planus, Meniere's Disease, Mixed Connective Tissue Disease,
Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia,
Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes,
Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary
Agammag-lobulinemia, Primary Biliary Cirrhosis, Psoriasis,
Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever,
Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiff-Man Syndrome,
Takayasu Arteritis, Temporal Arteritis, Giant Cell Arteritis,
Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo or Wegener's
Granulomatosis.
[0015] In a preferred embodiment, the multiple sclerosis is
relapsing-remitting multiple sclerosis or secondary progressive
multiple sclerosis.
[0016] In another preferred embodiment, the patient to be treated
is a human, including adults, adolescents, children, and
infants.
[0017] A second embodiment of the invention encompasses a method of
treating, preventing or managing an autoimmune disorder comprising
administering to a patient in need of such treatment a
therapeutically or prophylactively effective amount of clofarabine
or a pharmaceutically acceptable salt, solvate, hydrate, or
clathrate thereof and an additional therapeutic agent. In a
preferred embodiment, the additional therapeutic agent is an
antibiotic, an antiemetic agent, an antidepressant, and antifungal
agent, an antiinflammatory agent, an antiviral agent, an
immunomodulatory agent, a .beta.-Interferon, an alkylating agent, a
hormone or a cytokine.
[0018] A third embodiment of the invention encompasses a method of
reducing or avoiding adverse effects of traditional therapies for
autoimmune disorders which comprises administering to a patient in
need of such relief a therapeutically or prophylactively effective
amount of clofarabine or a pharmaceutically acceptable salt,
solvate, hydrate, or clathrate thereof. Examples of adverse effects
include, but are not limited to, nausea, reversible kidney
dysfunction, depression, herpes zoster infection and skin rash.
[0019] Similarly, the dosing regimens avoid or reduce the side or
adverse or unwanted effects associated with the administration of
purine nucleoside analogues such as fludarabine and cladribine.
3.1 Definitions
[0020] As used herein, the term "patient" means an animal (e.g.,
cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse,
rat, rabbit, guinea pig, etc.), preferably a mammal such as a
non-primate and a primate (e.g., monkey and human), most preferably
a human. In certain embodiments, the patient is an infant, child,
adolescent or adult.
[0021] As used herein, a "therapeutically effective amount" refers
to that amount of the compound of the invention or other active
ingredient sufficient to provide a therapeutic benefit in the
treatment or management of the disease or to delay or minimize
symptoms associated with the disease. Further, a therapeutically
effective amount with respect to a compound of the invention means
that amount of therapeutic agent alone, or in combination with
other therapies, that provides a therapeutic benefit in the
treatment or management of the disease. Used in connection with an
amount of a compound of the invention, the term can encompass an
amount that improves overall therapy, reduces or avoids symptoms or
causes of disease, or enhances the therapeutic efficacy of or
synergies with another therapeutic agent.
[0022] As used herein, a "prophylactically effective amount" refers
to that amount of a compound of the invention or other active
ingredient sufficient to result in the prevention, recurrence or
spread of the disease. A prophylactically effective amount may
refer to the amount sufficient to prevent initial disease or the
recurrence or spread of the disease or the occurrence of the
disease in a patient, including but not limited to those
predisposed to the disease. A prophylactically effective amount may
also refer to the amount that provides a prophylactic benefit in
the prevention of the disease. Further, a prophylactically
effective amount with respect to a compound of the invention means
that amount alone, or in combination with other agents, that
provides a prophylactic benefit in the prevention of the disease.
Used in connection with an amount of a compound of the invention,
the term can encompass an amount that improves overall prophylaxis
or enhances the prophylactic efficacy of or synergies with another
prophylactic agent.
[0023] As used herein, a "therapeutic protocol" refers to a regimen
of timing and dosing of one or more therapeutic agents.
[0024] As used herein, a "prophylactic protocol" refers to a
regimen of timing and dosing of one or more prophylactic
agents.
[0025] A used herein, a "protocol" includes dosing schedules and
dosing regimens. As used herein, "in combination" refers to the use
of more than one prophylactic and/or therapeutic agents.
[0026] As used herein, the terms "manage", "managing" and
"management" refer to the beneficial effects that a subject derives
from a prophylactic or therapeutic agent, which does not result in
a cure of the disease. In certain embodiments, a subject is
administered one or more prophylactic or therapeutic agents to
"manage" a disease so as to prevent the progression or worsening of
the disease.
[0027] As used herein, the terms "prevent", "preventing" and
"prevention" refer to the prevention of the onset recurrence,
spread or of the disease in a subject resulting from the
administration of a prophylactic or therapeutic agent.
[0028] As used herein, the terms "treat", "treating" and
"treatment" refer to the eradication or amelioration of the disease
or symptoms associated with the disease. In certain embodiments,
such terms refer to minimizing the spread or worsening of the
disease resulting from the administration of one or more
prophylactic or therapeutic agents to a subject with such a
disease.
[0029] As used herein, the term "pharmaceutically acceptable salts"
refer to salts prepared from pharmaceutically acceptable non-toxic
acids or bases including inorganic acids and bases and organic
acids and bases. Suitable pharmaceutically acceptable base addition
salts for the compound of the present invention include, but are
not limited to, metallic salts made from aluminum, calcium,
lithium, magnesium, potassium, sodium and zinc or organic salts
made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine,
choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Suitable non-toxic acids include,
but are not limited to, inorganic and organic acids such as acetic,
alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic,
citric, ethenesulfonic, formic, fumaric, furoic, galacturonic,
gluconic, glucuronic, glutamic, glycolic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,
phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,
sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific
non-toxic acids include hydrochloric, hydrobromic, phosphoric,
sulfuric, and methanesulfonic acids. Examples of specific salts
thus include hydrochloride and mesylate salts.
[0030] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide an active compound, particularly a compound
of the invention. Examples of prodrugs include, but are not limited
to, derivatives and metabolites of a compound of the invention that
include biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Preferably, prodrugs of compounds with carboxyl
functional groups are the lower alkyl esters of the carboxylic
acid. The carboxylate esters are conveniently formed by esterifying
any of the carboxylic acid moieties present on the molecule.
Prodrugs can typically be prepared using well-known methods, such
as those described by Burger's Medicinal Chemistry and Drug
Discovery 6th ed. (Donald J. Abraham ed., 2001, Wiley) and Design
and Application of Prodrugs (H. Bundgaard ed., 1985, Harwood
Academic Publishers Gmfh).
[0031] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide,"
"biohydrolyzable phosphate" mean an amide, ester, carbamate,
carbonate, ureide, or phosphate, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, alkoxyacyloxy
esters, alkyl acylamino alkyl esters, and choline esters. Examples
of biohydrolyzable amides include, but are not limited to, lower
alkyl amides, .alpha.-amino acid amides, alkoxyacyl amides, and
alkylaminoalkylcarbonyl amides. Examples of biohydrolyzable
carbamates include, but are not limited to, lower alkylamines,
substituted ethylenediamines, aminoacids, hydroxyalkylamines,
heterocyclic and heteroaromatic amines, and polyether amines.
[0032] As used herein and unless otherwise indicated, the term
"metabolite" means the product of metabolism of a compound of the
invention, e.g., a metabolite is a compound formed by hydrolysis,
oxidation, or other in vivo reaction, particularly in the liver. In
other words, the invention contemplates the synthesis and
administration of compounds that are in vivo metabolites of
clofarabine. Examples of metabolites include, but are not limited
to, derivatives of a compound of the invention that include
biohydrolyzable moieties such as biohydrolyzable amides,
biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable
carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate
analogues. Preferably, metabolites of compounds of the invention
are monophosphates, diphosphates and triphosphates, more preferably
triphosphates.
[0033] As used herein and unless otherwise indicated, the term
"optically pure" or "stereomerically pure" means a composition that
comprises one stereoisomer of a compound and is substantially free
of other stereoisomers of that compound. For example, a
stereomerically pure composition of a compound having one chiral
center will be substantially free of the opposite enantiomer of the
compound. Furthermore, the sugar moiety of the nucleoside analog
can exist in either the D or L forms of the sugar. As such, for
example, a stereomerically pure composition of a D compound will be
substantially free of the L form of the compound. A stereomerically
pure composition of a compound having two chiral centers will be
substantially free of other diastereomers of the compound. A
typical stereomerically pure compound comprises greater than about
80% by weight of one stereoisomer of the compound and less than
about 20% by weight of other stereoisomers of the compound, more
preferably greater than about 90% by weight of one stereoisomer of
the compound and less than about 10% by weight of the other
stereoisomers of the compound, even more preferably greater than
about 95% by weight of one stereoisomer of the compound and less
than about 5% by weight of the other stereoisomers of the compound,
and most preferably greater than about 97% by weight of one
stereoisomer of the compound and less than about 3% by weight of
the other stereoisomers of the compound.
[0034] As used herein and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of
a compound having one chiral center.
[0035] As used herein, the term "connective tissue" means tissue in
the body that maintains the form of the body and its organs and
provides cohesion and internal support, such as bone, ligaments,
tendons, cartilage, adipose tissue, and aponeuroses.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1 The Compound of the Invention
Clofarabine
[0036] The invention encompasses the use of clofarabine in the
methods, compositions and dosage forms described herein. It should
be recognized by one of skill in the art that the invention
encompasses pharmaceutically acceptable salts, hydrates,
clathrates, polymorphs, prodrugs, and stereoisomers of clofarabine,
including both the D and L isomers of the sugar moeity as well as
metabolites. Clofarabine is readily prepared using the methods in
U.S. Pat. Nos. 5,034,518, 5,384,310, and 5,661,136 which are
incorporated herein by reference. Alternatively, clofarabine is
commercially available and can be purchased.
[0037] Stereochemically pure compounds can be obtained from the
racemic compound by techniques known in the art. Examples include,
but are not limited to, the formation of chiral salts and the use
of chiral or high performance liquid chromatography "HPLC" and the
formation and crystallization of chiral salts. See, e.g., Jacques,
J., et al., Enantiomers, Racemates and Resolutions
(Wiley-Interscience, New York, 1981); Wilen, S. H., et al.,
Tetrahedron 33:2725 (1977); Eliel, E. L., Stereochemistry of Carbon
Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H., Tables of
Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,
Univ. of Notre Dame Press, Notre Dame, Ind., 1972).
[0038] Prodrugs and metabolites of Clofarabine can be readily
produced by methods well known in the art such as those described
by Burger's Medicinal Chemistry and Drug Discovery 6th ed. (Donald
J. Abraham ed., 2001, Wiley) and Design and Application of Prodrugs
(H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).
Particular metabolites of clofarabine encompassed by the invention
are clofarabine phosphate, clofarabine diphosphate and clofarabine
triphosphate. In a preferred embodiment of the invention, the
metabolite is clofarabine triphosphate.
4.2 Methods of Use
[0039] The invention encompasses methods of treating, preventing or
managing autoimmune diseases or disorders in a patient which
comprise administering to a patient in need of such treatment or
prevention a therapeutically effective amount of clofarabine, or a
pharmaceutically acceptable prodrug, stereoisomer, salt, solvate,
hydrate, or clathrate thereof.
[0040] Autoimmune disorders within the scope of the methods of the
invention are those which target the nervous system, the blood, the
gastrointestinal system, the endocrine glands, the skin, the
musculoskeletal system, the connective tissue or combinations
thereof. Specific autoimmune diseases or disorders within the scope
of the methods of the invention are: Alopecia Areata, Ankylosing
Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's
Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis,
Autoimmune Uveitis, Autoimmune Oophoritis, Autoimmune Orchitis,
Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac
Sprue-Dermatitis, Chronic Fatigue Immune Dysfunction Syndrome
(CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy,
Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome,
Cold Agglutinin Disease, Crohn's Disease, Dermatitis Herpetiformis,
Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis,
Graves' Disease, Guillain-Barre, Hashimoto's Thyroiditis,
Idiopathic Pulmonary Fibrosis, Idiopathic Thrombocytopenia Purpura
(ITP), IgA Nephropathy, Insulin dependent Diabetes, Immune Mediated
Diabetes, Juvenile Arthritis, Lichen Planus, Meniere's Disease,
Mixed Connective Tissue Disease, Myasthenia Gravis, Pemphigus
Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis,
Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and
Dermatomyositis, Primary Agammag-lobulinemia, Primary Biliary
Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome,
Rheumatic Fever, Sarcoidosis, Scleroderma, Sjogren's Syndrome,
Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis, Giant
Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo
or Wegener's Granulomatosis.
[0041] In other embodiments, diseases to be treated or prevented by
administering to a patient in need thereof an effective amount of
clofarabine include Alopecia Areata, Ankylosing Spondylitis,
Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune
Hemolytic Anemia, Autoimmune Hepatitis, Autoimmune Uveitis,
Autoimmune Oophoritis, Autoimmune Orchitis, Behcet's Disease,
Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis,
Chronic Fatigue Immune Dysfunction Syndrome (CFIDS), Chronic
Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome,
Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease,
Crohn's Disease, Dermatitis Herpetiformis, Essential Mixed
Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease,
Guillain-Barre, Hashimoto's Thyroiditis, Idiopathic Pulmonary
Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA
Nephropathy, Insulin dependent Diabetes, Immune Mediated Diabetes,
Juvenile Arthritis, Lichen Planus, Meniere's Disease, Mixed
Connective Tissue Disease, Myasthenia Gravis, Pemphigus Vulgaris,
Pernicious Anemia, Polyarteritis Nodosa, Polychondritis,
Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and
Dermatomyositis, Primary Agammag-lobulinemia, Primary Biliary
Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome,
Rheumatic Fever, Sarcoidosis, Scleroderma, Sjogren's Syndrome,
Stiff-Man Syndrome, Takayasu Arteritis, Temporal Arteritis, Giant
Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo
or Wegener's Granulomatosis.
[0042] In preferred embodiments of the invention, the multiple
sclerosis is relapsing-remitting multiple sclerosis or secondary
progressive multiple sclerosis.
[0043] Specific methods of the invention further comprise the
administration of an additional therapeutic agent (i.e. a
therapeutic agent other than a compound of the invention) In
certain embodiments of the present invention, the compounds of the
invention can be used in combination with at least one other
therapeutic agent. Therapeutic agents include, but are not limited
to antibiotics, antiemetic agents, antidepressants, and antifungal
agents, antiinflammatory agents, antiviral agents, immunomodulatory
agents, .beta.-interferons, alykylating agents, hormones or
cytokines.
[0044] In certain embodiments, clofarabine can be administered or
formulated in combination with antibiotics. In certain embodiments,
the antibiotic is a macrolide (e.g., tobramycin (Tobi.RTM.)), a
cephalosporin (e.g., cephalexin (Keflex.RTM.), cephradine
(Velosef.RTM.), cefuroxime (Ceftin.RTM.)), cefprozil
(Cefzil.RTM.)), cefaclor (Ceclor.RTM.), cefixime (Suprax.RTM.) or
cefadroxil (Duricef.RTM.)), a clarithromycin (e.g. clarithromycin
(Biaxin.RTM.)), an erythromycin (e.g., erythromycin (EMycin.RTM.)),
a penicillin (e.g., penicillin V (V-Cillin K.RTM. or Pen Vee
K.RTM.)) or a quinolone (e.g., ofloxacin (Floxin.RTM.),
ciprofloxacin (Cipro.RTM.) or norfloxacin (Noroxin.RTM.)),
aminoglycoside antibiotics (e.g., apramycin, arbekacin,
bambermycins, butirosin, dibekacin, neomycin, neomycin,
undecylenate, netilmicin, paromomycin, ribostamycin, sisomicin, and
spectinomycin), amphenicol antibiotics (e.g., azidamfenicol,
chloramphenicol, florfenicol, and thiamphenicol), ansamycin
antibiotics (e.g., rifamide and rifampin), carbacephems (e.g.,
loracarbef), carbapenems (e.g., biapenem and imipenem),
cephalosporins (e.g., cefaclor, cefadroxil, cefamandole,
cefatrizine, cefazedone, cefozopran, cefpimizole, cefpiramide, and
cefpirome), cephamycins (e.g., cefbuperazone, cefmetazole, and
cefminox), monobactams (e.g., aztreonam, carumonam, and tigemonam),
oxacephems (e.g., flomoxef, and moxalactam), penicillins (e.g.,
amdinocillin, amdinocillin pivoxil, amoxicillin, bacampicillin,
benzylpenicillinic acid, benzylpenicillin sodium, epicillin,
fenbenicillin, floxacillin, penamccillin, penethamate hydriodide,
penicillin o-benethamine, penicillin 0, penicillin V, penicillin V
benzathine, penicillin V hydrabamine, penimepicycline, and
phencihicillin potassium), lincosamides (e.g., clindamycin, and
lincomycin), macrolides (e.g., azithromycin, carbomycin,
clarithomycin, dirithromycin, erythromycin, and erylromycin
acistrate), amphomycin, bacitracin, capreomycin, colistin,
enduracidin, enviomycin, tetracyclines (e.g., apicycline,
chlortetracycline, clomocycline, and demeclocycline),
2,4-diaminopyrimidines (e.g., brodimoprim), nitrofurans (e.g.,
furaltadone, and furazolium chloride), quinolones and analogs
thereof (e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine,
and grepagloxacin), sulfonamides (e.g., acetyl
sulfamethoxypyrazine, benzylsulfamide, noprylsulfamide,
phthalylsulfacetamide, sulfachrysoidine, and sulfacytine), sulfones
(e.g., diathymosulfone, glucosulfone sodium, and solasulfone),
cycloserine, mupirocin and tuberin.
[0045] In certain embodiments, clofarabine can be administered or
formulated in combination with an antiemetic agent. Suitable
antiemetic agents include, but are not limited to, metoclopromide,
domperidone, prochlorperazine, promethazine, chlorpromazine,
trimethobenzamide, ondansetron, granisetron, hydroxyzine,
acethylleucine monoethanolamine, alizapride, azasetron,
benzquinamide, bietanautine, bromopride, buclizine, clebopride,
cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,
methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,
scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,
thioproperazine, tropisetron, and mixtures thereof.
[0046] In certain embodiments, clofarabine can be administered or
formulated in combination with an antidepressant. Suitable
antidepressants include, but are not limited to, binedaline,
caroxazone, citalopram, dimethazan, fencamine, indalpine,
indeloxazine hydrocholoride, nefopam, nomifensine, oxitriptan,
oxypertine, paroxetine, sertraline, thiazesim, trazodone,
benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide,
octamoxin, phenelzine, cotinine, rolicyprine, rolipram,
maprotiline, metralindole, mianserin, mirtazepine, adinazolam,
amitriptyline, amitriptylinoxide, amoxapine, butriptyline,
clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine,
dothiepin, doxepin, fluacizine, imipramine, imipramine N-oxide,
iprindole, lofepramine, melitracen, metapramine, nortriptyline,
noxiptilin, opipramol, pizotyline, propizepine, protriptyline,
quinupramine, tianeptine, trimipramine, adrafinil, benactyzine,
bupropion, butacetin, dioxadrol, duloxetine, etoperidone,
febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,
hematoporphyrin, hypericin, levophacetoperane, medifoxamine,
milnacipran, minaprine, moclobemide, nefazodone, oxaflozane,
piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole,
rubidium chloride, sulpirde, tandospirone, thozalinone, tofenacin,
toloxatone, tranylcypromine, L-tryptophan, venlafaxine, viloxazine,
and zimeldine.
[0047] In certain embodiments, clofarabine can be administered or
formulated in combination with an antifungal agent. Suitable
antifungal agents include but are not limited to amphotericin B,
itraconazole, ketoconazole, fluconazole, intrathecal, flucytosine,
miconazole, butoconazole, clotrimazole, nystatin, terconazole,
tioconazole, ciclopirox, econazole, haloprogrin, naftifine,
terbinafine, undecylenate, and griseofuldin.
[0048] In certain embodiments, clofarabine can be administered or
formulated in combination with an antiinflammatory agent. Useful
anti-inflammatory agents include, but are not limited to,
non-steroidal anti-inflammatory drugs such as salicylic acid,
acetylsalicylic acid, methyl salicylate, diflunisal, salsalate,
olsalazine, sulfasalazine, acetaminophen, indomethacin, sulindac,
etodolac, mefenamic acid, meclofenamate sodium, tolmetin,
ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium,
fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam,
meloxicam, ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome,
phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, apazone
and nimesulide; leukotriene antagonists including, but not limited
to, zileuton, aurothioglucose, gold sodium thiomalate and
auranofin; and other anti-inflammatory agents including, but not
limited to, methotrexate, colchicine, allopurinol, probenecid,
sulfinpyrazone and benzbromarone.
[0049] In certain embodiments, clofarabine can be administered or
formulated in combination with an antiviral agent. Useful antiviral
agents include, but are not limited to, nucleoside analogs, such as
zidovudine, acyclovir, gangcyclovir, vidarabine, idoxuridine,
trifluridine, and ribavirin, as well as foscarnet, amantadine,
rimantadine, saquinavir, indinavir, ritonavir, and the
alpha-interferons.
[0050] Examples of immunomodulatory agents include, but are not
limited to, methotrexate, leflunomide, cyclophosphamide,
cyclosporine A, macrolide antibiotics (e.g., FK506 (tacrolimus)),
methylprednisolone (MP), corticosteroids, steroids, mycophenolate
mofetil, rapamycin (sirolimus), mizoribine, deoxyspergualin,
brequinar, malononitriloamindes (e.g., leflunamide), T cell
receptor modulators, and cytokine receptor modulators.peptide
mimetics, and antibodies (e.g., human, humanized, chimeric,
monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments or
epitope binding fragments), nucleic acid molecules (e.g., antisense
nucleic acid molecules and triple helices), small molecules,
organic compounds, and inorganic compounds. In particular,
immunomodulatory agents include, but are not limited to,
methotrexate, leflunomide, cyclophosphamide, cytoxan, Immuran,
cyclosporine A, minocycline, azathioprine, antibiotics (e.g., FK506
(tacrolimus)), methylprednisolone (MP), corticosteroids, steroids,
mycophenolate mofetil, rapamycin (sirolimus), mizoribine,
deoxyspergualin, brequinar, malononitriloamindes (e.g.,
leflunamide), T cell receptor modulators, and cytokine receptor
modulators.
[0051] Examples of T cell receptor modulators include, but are not
limited to, anti-T cell receptor antibodies (e.g., anti-CD4
antibodies (e.g., cM-T412 (Boeringer), IDEC-CE9.1 (IDEC and SKB),
mAB 4162W94, Orthoclone and OKTcdr4a (Janssen-Cilag)), anti-CD3
antibodies (e.g., Nuvion (Product Design Labs), OKT3 (Johnson &
Johnson), or Rituxan (IDEC)), anti-CD5 antibodies (e.g., an
anti-CD5 ricin-linked immunoconjugate), anti-CD7 antibodies (e.g.,
CHH-380 (Novartis)), anti-CD8 antibodies, anti-CD40 ligand
monoclonal antibodies (e.g., IDEC-131 (IDEC)), anti-CD52 antibodies
(e.g., CAMPATH 1H (Ilex)), anti-CD2 antibodies, anti-CD11a
antibodies (e.g., Xanelim (Genentech)), and anti-B7 antibodies
(e.g., IDEC-114) (IDEC))) and CTLA4-immunoglobulin. In a specific
embodiment, a T cell receptor modulator is a CD2 antagonist. In
other embodiments, a T cell receptor modulator is not a CD2
antagonist. In another specific embodiment, a T cell receptor
modulator is a CD2 binding molecule, preferably MEDI-507. In other
embodiments, a T cell receptor modulator is not a CD2 binding
molecule.
[0052] Examples of cytokine receptor modulators include, but are
not limited to, soluble cytokine receptors (e.g., the extracellular
domain of a TNF-.alpha.receptor or a fragment thereof, the
extracellular domain of an IL-1.beta. receptor or a fragment
thereof, and the extracellular domain of an IL-6 receptor or a
fragment thereof), cytokines or fragments thereof (e.g.,
interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,
IL-10, IL-11, IL-12, IL-15, TNF-.alpha., TNF-.alpha., interferon
(IFN)-.alpha., IFN-.beta., IFN-.gamma., and GM-CSF), anti-cytokine
receptor antibodies (e.g., anti-IFN receptor antibodies, anti-IL-2
receptor antibodies (e.g., Zenapax (Protein Design Labs)),
anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies,
anti-IL-10 receptor antibodies, and anti-IL-12 receptor
antibodies), anti-cytokine antibodies (e.g., anti-IFN antibodies,
anti-TNF-.alpha. antibodies, anti-IL-1.beta. antibodies, anti-IL-6
antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)), and
anti-IL-12 antibodies). In a specific embodiment, a cytokine
receptor modulator is IL-4, IL-10, or a fragment thereof. In
another embodiment, a cytokine receptor modulator is an
anti-IL-1.beta. antibody, anti-IL-6 antibody, anti-IL-12 receptor
antibody, or anti-TNF-.alpha. antibody. In another embodiment, a
cytokine receptor modulator is the extracellular domain of a
TNF-.alpha. receptor or a fragment thereof. In certain embodiments,
a cytokine receptor modulator is not a TNF-.alpha. antagonist.
[0053] In a preferred embodiment, proteins, polypeptides or
peptides (including antibodies) that are utilized as
immunomodulatory agents are derived from the same species as the
recipient of the proteins, polypeptides or peptides so as to reduce
the likelihood of an immune response to those proteins,
polypeptides or peptides. In another preferred embodiment, when the
subject is a human, the proteins, polypeptides, or peptides that
are utilized as immunomodulatory agents are human or humanized.
[0054] Examples of cytokines include, but are not limited to,
interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4),
interleukin-5 (IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7),
interleukin-9 (IL-9), interleukin-10 (IL-10), interleukin-12
(IL-12), interleukin 15 (IL-15), interleukin 18 (IL-18), platelet
derived growth factor (PDGF), erythropoietin (Epo), epidermal
growth factor (EGF), fibroblast growth factor (FGF), granulocyte
macrophage stimulating factor (GM-CSP), granulocyte colony
stimulating factor (G-CSF), macrophage colony stimulating factor
(M-CSF), prolactin, and interferon (IFN), e.g., IFN-alpha, and
IFN-gamma).
[0055] Examples of hormones include, but are not limited to,
luteinizing hormone releasing hormone (LHRH), growth hormone (GH),
growth hormone releasing hormone, ACTH, somatostatin, somatotropin,
somatomedin, parathyroid hormone, hypothalamic releasing factors,
insulin, glucagon, enkephalins, vasopressin, calcitonin, heparin,
low molecular weight heparins, heparinoids, synthetic and natural
opioids, insulin thyroid stimulating hormones, and endorphins.
[0056] Examples of .beta.-interferons include, but are not limited
to, interferon beta-1a and interferon beta1-b.
[0057] Examples of alkylating agents include, but are not limited
to nitrogen mustards, ethylenimines, methylmelamines, alkyl
sulfonates, nitrosoureas, triazenes, mechlorethamine,
cyclophosphamide, ifosfamide, melphalan, chlorambucil,
hexamethylmelaine, thiotepa, busulfan, carmustine, streptozocin,
dacarbazine and temozolomide.
[0058] Clofarabine and the other therapeutics agent can act
additively or, more preferably, synergistically. In a preferred
embodiment, a composition comprising a compound of the invention is
administered concurrently with the administration of another
therapeutic agent, which can be part of the same composition or in
a different composition from that comprising the compounds of the
invention. In another embodiment, a compound of the invention is
administered prior to or subsequent to administration of another
therapeutic agent.
4.3 Doses and Dosage Forms
[0059] The magnitude of a prophylactic or therapeutic dose of
clofarabine or a pharmaceutically acceptable salt, solvate,
hydrate, clathrate, prodrug, metabolite or stereoisomer thereof in
the acute or chronic management of a disease or condition will
vary, however, with the nature and severity of the disease or
condition, and the route by which the active ingredient is
administered. The dose, and perhaps the dose frequency, will also
vary according to the disease to be treated, the age, body weight,
and response of the individual patient. Suitable dosing regimens
can be readily selected by those skilled in the art with due
consideration of such factors. In one embodiment, the dose of
clofarabine is greater than about 0.04 mg/kg/day, preferably
greater than 0.20 mg/kg/day, most preferably greater than 1
mg/kg/day. In general, the recommended daily dose range for the
conditions described herein lie within the range of from about 1.25
mg/kg to about 80 mg/kg per day, given as a single once-a-day dose,
preferably as divided doses throughout a day. Additionally, the
recommended daily dose ran can be administered in cycles as single
agents or in combination with other therapeutic agents. In one
embodiment, the daily dose is administered in a single dose or in
equally divided doses. Specifically, a daily dose range should be
from about 5 mg/kg to about 75 mg/kg per day, more specifically,
between about 20 mg/kg and about 60 mg/kg per day, most
specifically between about 40 mg/kg and 50 mg/kg per day. In
managing the patient, the therapy should be initiated at a lower
dose, perhaps about 1.25 mg/kg to about 25 mg/kg per day, and
increased if necessary up to about 40 mg/kg to about 50 mg/kg per
day as either a single dose or divided doses, depending on the
patient's global response. In the treatment of chronic diseases and
disorders, the recommended daily dose range for the conditions
described herein lie within the range of from about 1.25 mg/kg to
about 10 mg/kg per day, given as a single once-a-day dose,
preferably as divided doses throughout a day. Specifically, a daily
dose range for chronic conditions should be from about 2 mg/kg to
about 6 mg/kg per day, more specifically, between about 4 mg/kg and
about 5 mg/kg per day.
[0060] It may be necessary to use dosages of the active ingredient
outside the ranges disclosed herein in some cases, as will be
apparent to those of ordinary skill in the art, but the dosage
should not fall below 1.0 mg/kg/day. The maximum tolerated doses of
clofarabine is approximately 80 mg/kg per day. Furthermore, it is
noted that the clinician or treating physician will know how and
when to interrupt, adjust, or terminate therapy in conjunction with
individual patient response.
[0061] Different therapeutically effective amounts may be
applicable for different diseases and conditions, as will be
readily known by those of ordinary skill in the art. Similarly,
amounts sufficient to treat or prevent such diseases, but
insufficient to cause, or sufficient to reduce, adverse effects
associated with conventional therapies are also encompassed by the
above described dosage amounts and dose frequency schedules.
[0062] In a preferred embodiment, the invention encompasses a
method for treating, preventing, or managing multiple sclerosis
utilizing doses higher than 1 mg/kg per day, preferably higher than
1.25 mg/kg per day.
4.4 Pharmaceutical Compositions
[0063] Pharmaceutical compositions and single unit dosage forms
comprising clofarabine,
or a pharmaceutically acceptable polymorph, prodrug, salt,
stereoisomer, solvate, hydrate, or clathrate thereof, are also
encompassed by the invention. Individual dosage forms of the
invention may be suitable for oral, mucosal (including sublingual,
buccal, rectal, nasal, or vaginal), parenteral (including
subcutaneous, intramuscular, bolus injection, intraarterial, or
intravenous), transdermal, or topical administration.
[0064] Pharmaceutical compositions and dosage forms of the
invention comprise clofarabine, or a pharmaceutically acceptable
prodrug, polymorph, salt, stereoisomer, solvate, hydrate, or
clathrate thereof. Pharmaceutical compositions and dosage forms of
the invention typically also comprise one or more pharmaceutically
acceptable excipients.
[0065] A particular pharmaceutical composition encompassed by this
embodiment comprises clofarabine, or a pharmaceutically acceptable
polymorph, prodrug, salt, solvate, hydrate, or clathrate thereof,
and at least one additional therapeutic agent. Examples of
additional therapeutic agents include, but are not limited to,
those listed above in section 4.2.
[0066] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; ointments; cataplasms (poultices); pastes; powders;
dressings; creams; plasters; solutions; patches; aerosols (e.g.,
nasal sprays or inhalers); gels; liquid dosage forms suitable for
oral or mucosal administration to a patient, including suspensions
(e.g., aqueous or non-aqueous liquid suspensions, oil-in-water
emulsions, or a water-in-oil liquid emulsions), solutions, and
elixirs; liquid dosage forms suitable for parenteral administration
to a patient; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0067] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease or a related
disease may contain larger amounts of one or more of the active
ingredients it comprises than a dosage form used in the chronic
treatment of the same disease. Similarly, a parenteral dosage form
may contain smaller amounts of one or more of the active
ingredients it comprises than an oral dosage form used to treat the
same disease or disorder. These and other ways in which specific
dosage forms encompassed by this invention will vary from one
another will be readily apparent to those skilled in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).
[0068] Typical pharmaceutical compositions and dosage forms
comprise one or more carriers, excipients or diluents. Suitable
excipients are well known to those skilled in the art of pharmacy,
and non-limiting examples of suitable excipients are provided
herein. Whether a particular excipient is suitable for
incorporation into a pharmaceutical composition or dosage form
depends on a variety of factors well known in the art including,
but not limited to, the way in which the dosage form will be
administered to a patient. For example, oral dosage forms such as
tablets may contain excipients not suited for use in parenteral
dosage forms. The suitability of a particular excipient may also
depend on the specific active ingredients in the dosage form.
[0069] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., fens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0070] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0071] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g. vials), blister packs, and
strip packs.
[0072] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0073] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise clofarabine, or a pharmaceutically
acceptable salt, solvate, clathrate, hydrate, polymorph or prodrug
thereof lie within the range of from 5 mg/kg to about 75 mg/kg per
day, more specifically, between about 20 mg/kg and about 60 mg/kg
per day, most specifically between about 40 mg/kg and 50 mg/kg per
day.
4.4.1 Oral Dosage Forms
[0074] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0075] Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0076] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0077] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0078] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0079] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g. granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0080] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0081] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
specifically from about 1 to about 5 weight percent of
disintegrant.
[0082] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, pre-gelatinized starch, other starches, clays, other
algins, other celluloses, gums, and mixtures thereof.
[0083] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
4.4.2 Delayed Release Dosage Forms
[0084] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0085] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0086] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
4.4.3 Parenteral Dosage Forms
[0087] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection (reconstitutable powders),
suspensions ready for injection, and emulsions.
[0088] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0089] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention.
4.4.4 Transdermal and Topical Dosage Forms
[0090] Transdermal and topical dosage forms of the invention
include, but are not limited to, creams, lotions, ointments, gels,
solutions, emulsions, suspensions, or other forms known to one of
skill in the art. See, e.g., Remington's Pharmaceutical Sciences,
18th eds., Mack Publishing, Easton Pa. (1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985). Transdermal dosage forms include "reservoir
type" or "matrix type" patches, which can be applied to the skin
and worn for a specific period of time to permit the penetration of
a desired amount of active ingredients.
[0091] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal and topical
dosage forms encompassed by this invention are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied. With that fact in mind, typical excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
lotions, tinctures, creams, emulsions, gels or ointments, which are
non-toxic and pharmaceutically acceptable. Moisturizers or
humectants can also be added to pharmaceutical compositions and
dosage forms if desired. Examples of such additional ingredients
are well known in the art. See, e.g., Remington's Pharmaceutical
Sciences, 118th eds., Mack Publishing, Easton Pa. (1990).
[0092] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone, various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
[0093] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
4.4.5 Mucosal Dosage Forms
[0094] Mucosal dosage forms of the invention include, but are not
limited to, ophthalmic solutions, sprays and aerosols, or other
forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa.
(1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,
Lea & Febiger, Philadelphia (1985). Dosage forms suitable for
treating mucosal tissues within the oral cavity can be formulated
as mouthwashes or as oral gels. In one embodiment, the aerosol
comprises a carrier. In another embodiment, the aerosol is carrier
free.
[0095] Clofarabine may also be administered directly to the lung by
inhalation. For administration by inhalation, clofarabine can be
conveniently delivered to the lung by a number of different
devices. For example, a Metered Dose Inhaler ("MDI") which utilizes
canisters that contain a suitable low boiling propellant, e.g.
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas can
be used to deliver a compound of formula I directly to the lung.
MDI devices are available from a number of suppliers such as 3M
Corporation, Aventis, Boehringer Ingleheim, Forest Laboratories,
Glaxo-Wellcome, Schering Plough and Vectura.
[0096] Alternatively, a Dry Powder Inhaler (DPI) device can be used
to administer a compound of formula I to the lung (See, e.g.,
Raleigh et al., Proc. Amer. Assoc. Cancer Research Annual Meeting,
1999, 40, 397, which is herein incorporated by reference). DPI
devices typically use a mechanism such as a burst of gas to create
a cloud of dry powder inside a container, which can then be inhaled
by the patient. DPI devices are also well known in the art and can
be purchased from a number of vendors which include, for example,
Fisons, Glaxo-Wellcome, Inhale Therapeutic Systems, ML
Laboratories, Qdose and Vectura. A popular variation is the
multiple dose DPI ("MDDPI") system, which allows for the delivery
of more than one therapeutic dose. MDDPI devices are available from
companies such as AstraZeneca, GlaxoWellcome, IVAX, Schering
Plough, SkyePharma and Vectura. For example, capsules and
cartridges of gelatin for use in an inhaler or insufflator can be
formulated containing a powder mix of the compound and a suitable
powder base such as lactose or starch for these systems.
[0097] Another type of device that can be used to deliver
clofarabine to the lung is a liquid spray device supplied, for
example, by Aradigm Corporation. Liquid spray systems use extremely
small nozzle holes to aerosolize liquid drug formulations that can
then be directly inhaled into the lung.
[0098] In a preferred embodiment, a nebulizer device is used to
deliver clofarabine to the lung. Nebulizers create aerosols from
liquid drug formulations by using, for example, ultrasonic energy
to form fine particles that can be readily inhaled (See e.g.
Verschoyle et al., British J Cancer, 1999, 80, Suppl 2, 96, which
is herein incorporated by reference). Examples of nebulizers
include devices supplied by Sheffield/Systemic Pulmonary Delivery
Ltd. (See, Armer et al., U.S. Pat. No. 5,954,047; van der Linden et
al., U.S. Pat. No. 5,950,619; van der Linden et al., U.S. Pat. No.
5,970,974, which are herein incorporated by reference), Aventis and
Batelle Pulmonary Therapeutics. Inhaled compound of formula I,
delivered by nebulizer devices, is currently under investigation as
a treatment for aerodigestive cancer (Engelke et al., Poster 342 at
American Association of Cancer Research, San Francisco, Calif.,
Apr. 1-5, 2000) and lung cancer (Dahl et al., Poster 524 at
American Association of Cancer Research, San Francisco, Calif.,
Apr. 1-5, 2000).
[0099] In a particularly preferred embodiment, an
electrohydrodynamic ("EHD") aerosol device is used to deliver
clofarabine to the lung. EHD aerosol devices use electrical energy
to aerosolize liquid drug solutions or suspensions (see e.g.,
Noakes et al., U.S. Pat. No. 4,765,539; Coffee, U.S. Pat. No.,
4,962,885; Coffee, PCT Application, WO 94/12285; Coffee, PCT
Application, WO 94/14543; Coffee, PCT Application, WO 95/26234,
Coffee, PCT Application, WO 95/26235, Coffee, PCT Application, WO
95/32807, which are herein incorporated by reference). The
electrochemical properties of the compound of formula I formulation
may be important parameters to optimize when delivering this drug
to the lung with an EHD aerosol device and such optimization is
routinely performed by one of skill in the art. EHD aerosol devices
may more efficiently delivery drugs to the lung than existing
pulmonary delivery technologies. Other methods of intra-pulmonary
delivery of clofarabine will be known to the skilled artisan and
are within the scope of the invention.
[0100] Liquid drug formulations suitable for use with nebulizers
and liquid spray devices and EHD aerosol devices will typically
include a compound of formula I with a pharmaceutically acceptable
carrier. Preferably, the pharmaceutically acceptable carrier is a
liquid such as alcohol, water, polyethylene glycol or a
perfluorocarbon. Optionally, another material may be added to alter
the aerosol properties of the solution or suspension of
clofarabine. Preferably, this material is liquid such as an
alcohol, glycol, polyglycol or a fatty acid. Other methods of
formulating liquid drug solutions or suspension suitable for use in
aerosol devices are known to those of skill in the art (See, e.g.,
Biesalski, U.S. Pat. Nos. 5,112,598; Biesalski, 5,556,611, which
are herein incorporated by reference) A compound of formula I can
also be formulated in rectal or vaginal compositions such as
suppositories or retention enemas, e.g., containing conventional
suppository bases such as cocoa butter or other glycerides.
[0101] In addition to the formulations described previously,
clofarabine can also be formulated as a depot preparation. Such
long acting formulations can be administered by implantation (for
example subcutaneously or intramuscularly) or by intramuscular
injection. Thus, for example, the compounds can be formulated with
suitable polymeric or hydrophobic materials (for example, as an
emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble
salt.
[0102] Alternatively, other pharmaceutical delivery systems can be
employed. Liposomes and emulsions are well known examples of
delivery vehicles that can be used to deliver clofarabine. Certain
organic solvents such as dimethylsulfoxide can also be employed,
although usually at the cost of greater toxicity. A compound of
formula I can also be delivered in a controlled release system. In
one embodiment, a pump can be used (Sefton, CRC Crit. Ref Biomed
Eng., 1987, 14, 201; Buchwald et al., Surgery, 1980, 88, 507;
Saudek et al., N. Engl. J. Med, 1989, 321, 574). In another
embodiment, polymeric materials can be used (see Medical
Applications of Controlled Release, Langer and Wise (eds.), CRC
Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability,
Drug Product Design and Performance, Smolen and Ball (eds.), Wiley,
New York (1984); Ranger and Peppas, 3 Macromol. Sci. Rev. Macromol.
Chem., 1983, 23, 61; see also Levy et al., Science 1985, 228, 190;
During et al., Arm. Neurol., 1989,25,351; Howard et al., 1989, J.
Neurosurg. 71, 105). In yet another embodiment, a
controlled-release system can be placed in proximity of the target
of the compounds of the invention, e.g., the lung, thus requiring
only a fraction of the systemic dose (see, e.g., Goodson, in
Medical Applications of Controlled Release, supra, vol. 2, pp. 115
(1984)). Other controlled-release system can be used (see e.g.
Langer, Science, 1990, 249, 1527).
[0103] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide mucosal dosage forms
encompassed by this invention are well known to those skilled in
the pharmaceutical arts, and depend on the particular site or
method which a given pharmaceutical composition or dosage form will
be administered. With that fact in mind, typical excipients
include, but are not limited to, water, ethanol, ethylene glycol,
propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl
palmitate, mineral oil, and mixtures thereof, which are non-toxic
and pharmaceutically acceptable. Examples of such additional
ingredients are well known in the art. See, e.g., Remington s
Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa.
(1990).
[0104] The pH of a pharmaceutical composition or dosage form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, can also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
[0105] This and other novel and unexpected advantages of the
invention are further illustrated by the following non-limiting
examples.
5. EXAMPLES
5.1 Example 1
Parenteral Dosage Formulation
[0106] Clofarabine, 9.86 g, is wetted/partially dissolved with 600
mL of a 9:1 mixture of tertiary butanol and Water for Injection USP
which is pre-cooled to 5.degree. C. Once the drug powder is
completely wetted, dissolution is completed by the addition of 600
mL of a 1:9 mixture of tertiary butanol and Water for Injection and
766 mL of a 1:1 mixture of tertiary butanol and Water for Injection
which likewise is pre-cooled to 5.degree. C. thereby making the
final solution a 1:1 mixture. The dissolution is carried out under
protection from light.
[0107] The solution formed above is promptly lyophilized in a
Virtis INOTOP lyophilizer at -16.degree. C. under light protectant
conditions over a period of 48 hours. The resultant lyophilized
product (lyophile) is then further dried at 15.degree. C. under
high vacuum for 48 hours. No detectable degradation of the drug is
observed during these procedures. The lyophile is packaged under
sterile conditions into 30 mL vials, each containing 50 mg of drug,
50 mg of mannitol and sodium hydroxide to adjust the pH to 7.7 and
standard excess to allow for vial/needle/syringe loss.
[0108] The lyophile is reconstituted with 2 mL of Water for
Injection USP, which typically will be supplied with the drug in a
separate vial, to achieve a final drug concentration of 25
mg/mL.
5.2 Example 2:25 Mg Dosage Capsule
[0109] Table 1 illustrates a batch formulation and a single dose
unit formulation containing 25 mg of Clofarabine.
TABLE-US-00001 TABLE 1 Formulation for 25 mg tablet Quantity
Quantity Material Percent by Weight (mg/tablet) (kg/batch)
Clofarabine 40% 25.00 20.00 Microcrystalline 53.5% 33.44 26.75
Cellulose, NF Pluronic F-68 4.0% 2.50 2.00 Surfactant
Croscarmellose 2.0% 1.25 1.00 Sodium Type A, NF Magnesium Stearate,
0.5% 0.3125 0.25 NF Total 100.0% 62.50 mg 50.00 kg
[0110] The microcrystalline cellulose, croscarmellose sodium, and
Clofarabine components are passed through a #30 mesh screen (about
430.mu. to about 655.mu.). The Pluronic F-68.RTM. (manufactured by
JRH Biosciences, Inc. of Lenexa, Kans.) surfactant is passed
through a #20 mesh screen (about 457.mu. to about 1041.mu.). The
Pluronic F-68.RTM. surfactant and 0.5 kgs of croscarmellose sodium
are loaded into a 16 qt. twin shell tumble blender and are mixed
for about 5 minutes. The mix is then transferred to a 3 cubic foot
twin shell tumble blender where the microcrystalline cellulose is
added and blended for about 5 minutes. The thalidomide is added and
blended for an additional 25 minutes. This pre-blend is passed
through a roller compactor with a hammer mill attached at the
discharge of the roller compactor and moved back to the tumble
blender. The remaining croscarmellose sodium and magnesium stearate
is added to the tumble blender and blended for about 3 minutes. The
final mixture is compressed on a rotary tablet press with 62.5 mg
per tablet (800,000 tablet batch size).
5.3 Example 3
50 Mg Dosage Capsule
[0111] Table 2 illustrates a batch formulation and a single dose
unit formulation containing 50 mg of Clofarabine.
TABLE-US-00002 TABLE 2 Formulation for 50 mg tablet Quantity
Quantity Material Percent by Weight (mg/tablet) (kg/batch)
Clofarabine 40% 50.00 20.00 Microcrystalline 53.5% 66.875 26.75
Cellulose, NF Pluronic F-68 4.0% 5.00 2.00 Surfactant
Croscarmellose 2.0% 2.50 1.00 Sodium Type A, NF Magnesium Stearate,
0.5% 0.625 0.25 NF Total 100.0% 125.00 mg 50.00 kg
[0112] The microcrystalline cellulose, croscarmellose sodium, and
Clofarabine components are passed through a #30 mesh screen (about
430.mu. to about 655.mu.). The Pluronic F-68.RTM. (manufactured by
JRH Biosciences, Inc. of Lenexa, Kans.) surfactant is passed
through a #20 mesh screen (about 457.mu. to about 1041.mu.). The
Pluronic F-680.RTM. surfactant and 0.5 kgs of croscarmellose sodium
are loaded into a 16 qt. twin shell tumble blender and are mixed
for about 5 minutes. The mix is then transferred to a 3 cubic foot
twin shell tumble blender where the microcrystalline cellulose is
added and blended for about 5 minutes. The thalidomide is added and
blended for an additional 25 minutes. This pre-blend is passed
through a roller compactor with a hammer mill attached at the
discharge of the roller compactor and moved back to the tumble
blender. The remaining croscarmellose sodium and magnesium stearate
is added to the tumble blender and blended for about 3 minutes. The
final mixture is compressed on a rotary tablet press with 125 mg
per tablet (400,000 tablet batch size).
5.4 Example 4
200 Mg Dosage Capsule
[0113] Table 3 illustrates a batch formulation and single dosage
formulation for a 200 mg Clofarabine single dose unit, i.e., about
40 percent by weight.
TABLE-US-00003 TABLE 3 Formulation for 200 mg capsule Quantity
Quantity Material Percent By Weigh (mg/tablet) (kg/batch)
Clofarabine 40.0% 200 mg 16.80 kg Pregelatinized Corn 9.5% 297.5 mg
24.99 kg Starch, NF5 Magnesium Stearate 0.5% 2.5 mg 0.21 kg Total
100.0% 500 mg 42.00 kg
[0114] The pregelatinized corn starch (SPRESS B-820) and
3-[2-(3'-methyl-biphen-4-yloxy)-acetylamino]-benzoic acid
components are passed through a 710 .mu.m screen and then are
loaded into a Diffusion Mixer with a baffle insert and blended for
15 minutes. The magnesium stearate is passed through a 210 .mu.L m
screen and is added to the Diffusion Mixer. The blend is then
encapsulated in a size #0 capsule, 500 mg per capsule (8400 capsule
batch size) using a Dosator type capsule filling machine.
5.5 Example 5
100 Mg Oral Dosage Form
[0115] Table 4 illustrates a batch formulation and a single dose
unit formulation containing 100 mg of Clofarabine.
TABLE-US-00004 TABLE 4 Formulation for 100 mg tablet Quantity
Quantity Material Percent by Weight (mg/tablet) (kg/batch)
Clofarabine 40% 100.00 20.00 Microcrystalline 53.5% 133.75 26.75
Cellulose, NF Pluronic F-68 4.0% 10.00 2.00 Surfactant
Croscarmellose 2.0% 5.00 1.00 Sodium Type A, NF Magnesium Stearate,
0.5% 1.25 0.25 NF Total 100.0% 250.00 mg 50.00 kg
[0116] The microcrystalline cellulose, croscarmellose sodium, and
Clofarabine components are passed through a #30 mesh screen (about
430.mu. to about 655.mu.). The Pluronic F-68.RTM. (manufactured by
JRH Biosciences, Inc. of Lenexa, Kans.) surfactant is passed
through a #20 mesh screen (about 457.mu. to about 1041.mu.). The
Pluronic F-68.RTM. surfactant and 0.5 kgs of croscarmellose sodium
are loaded into a 16 qt. twin shell tumble blender and are mixed
for about 5 minutes. The mix is then transferred to a 3 cubic foot
twin shell tumble blender where the microcrystalline cellulose is
added and blended for about 5 minutes. The thalidomide is added and
blended for an additional 25 minutes. This pre-blend is passed
through a roller compactor with a hammer mill attached at the
discharge of the roller compactor and moved back to the tumble
blender. The remaining croscarmellose sodium and magnesium stearate
is added to the tumble blender and blended for about 3 minutes. The
final mixture is compressed on a rotary tablet press with 250 mg
per tablet (200,000 tablet batch size).
5.6 Example 6
Aerosol Dosage Form
[0117] A concentrate is prepared by combining Clofarabine, and a
12.6 kg portion of the trichloromonofluoromethane in a sealed
stainless steel vessel equipped with a high shear mixer. Mixing is
carried out for about 20 minutes. The bulk suspension is then
prepared in the sealed vessel by combining the concentrate with the
balance of the propellants in a bulk product tank that is
temperature controlled to 21.degree. to 27.degree. C. and pressure
controlled to 2.8 to 4.0 BAR. 17 ml aerosol containers which have a
metered valve which is designed to provide 100 inhalations of the
composition of the invention. Each container is provided with the
following:
TABLE-US-00005 Clofarabine 0.0141 g trichloromonofluoromethane
1.6939 g dichlorodifluoromethane 3.7154 g dichlorotetrafluoroethane
1.5766 g total 7.0000 g
[0118] While the invention has been described with respect to the
particular embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made without
departing from the spirit and scope of the invention as defined in
the claims. Such modifications are also intended to fall within the
scope of the appended claims.
* * * * *